tbuckley/cabot-search huggingface dataset:
A novel polypeptide encoded by the circular RNA ZKSCAN1 suppresses HCC via degradation of mTOR
Authors: Runjie Song, Shuoqian Ma, Jiajia Xu, Xin Ren, Peilan Guo, Huijiao Liu, Peng Li, Fan Yin, Mei Liu, Qiang Wang, Lei Yu, Jiali Liu, Binwei Duan, Nafis A. Rahman, Sławomir Wołczyński, Guangming Li, Xiangdong Li
Journal: Molecular Cancer (2023)

hsa_circ_0001727 (circZKSCAN1) has been reported to be a tumor-associated circRNA by sponging microRNAs. Intriguingly, we found that circZKSCAN1 encoded a secretory peptide (circZKSaa) in the liver. The present study aims to elucidate the potential role and molecular mechanism of circZKSaa in the regulation of hepatocellular carcinoma (HCC) progression.The circRNA profiling datasets (RNA-seq data GSE143233 and GSE140202) were reanalyzed and circZKSCAN1 was selected for further study. Mass spectrometry, polysome fractionation assay, dual-luciferase reporter, and a series of experiments showed that circZKSCAN1 encodes circZKSaa. Cell proliferation, apoptosis, and tumorigenesis in nude mice were examined to investigate the functions of circZKSaa. Mechanistically, the relationship between the circZKSaa and mTOR in HCC was verified by immunoprecipitation analyses, mass spectrometry, and immunofluorescence staining analyses.Receiver operating characteristic (ROC) analysis demonstrated that the secretory peptide circZKSaa encoded by circZKSCAN1 might be the potential biomarker for HCC tissues. Through a series of experiments, we found that circZKSaa inhibited HCC progression and sensitize HCC cells to sorafenib. Mechanistically, we found that the sponge function of circZKSCAN1 to microRNA is weak in HCC, while overexpression of circZKSaa promoted the interaction of FBXW7 with the mammalian target of rapamycin (mTOR) to promote the ubiquitination of mTOR, thereby inhibiting the PI3K/AKT/mTOR pathway. Furthermore, we found that the high expression of cicZKSCAN1 in sorafenib-treated HCC cells was regulated by QKI-5.These results reveal that a novel circZKSCAN1-encoded peptide acts as a tumor suppressor on PI3K/AKT/mTOR pathway, and sensitizes HCC cells to sorafenib via ubiquitination of mTOR. These findings demonstrated that circZKSaa has the potential to serve as a therapeutic target and biomarker for HCC treatment.
Adaptation of the U.S.-oriented evidence-based intervention <i>TransAction</i> for transgender women in Vietnam
Authors: Cathy J. Reback, Chunqing Lin, Sherry Larkins, Vu Thi Tuong Vi, Nguyen Thi Ngoc Diep, Nguyen Ly Lai, Do Van Dung
Journal: International Journal of Transgender Health (2023)

Trans women in Vietnam are among the most vulnerable groups with high HIV risk and limited access to care.
Considerations for Drug Development in Myelodysplastic Syndromes
Authors: Mikkael A. Sekeres, Nina Kim, Amy E. DeZern, Kelly J. Norsworthy, Jacqueline S. Garcia, R. Angelo de Claro, Marc R. Theoret, Emily Y. Jen, Lori A. Ehrlich, Amer M. Zeidan, Rami S. Komrokji
Journal: Clinical Cancer Research (2023)

Myelodysplastic syndromes (MDS) have historically been challenging diseases for drug development due to their biology, preclinical modeling, and the affected patient population. In April 2022, the FDA convened a panel of regulators and academic experts in MDS to discuss approaches to improve MDS drug development. The panel reviewed challenges in MDS clinical trial design and endpoints and outlined considerations for future trial design in MDS to facilitate drug development to meaningfully meet patient needs. Challenges for defining clinical benefit in patients with MDS include cumbersome response criteria, standardized transfusion thresholds, and application and validation of patient reported outcome instruments. Clinical trials should reflect the biology of disease evolution, the advanced age of patients with MDS, and how patients are treated in real-world settings to maximize the likelihood of identifying active drugs. In patients with lower-risk disease, response criteria for anemic patients should be based on baseline transfusion dependency, improvement in symptoms, and quality of life. For higher-risk patients with MDS, trials should include guidance to prevent dose reductions or delays that could limit efficacy, specify minimal durations of treatment (in the absence of toxicity or progression), and have endpoints focused on overall survival and durable responses. MDS trials should be designed from the outset to allow the practicable application of new therapies in this high-needs population, with drugs that can be administered and tolerated in community settings, and with endpoints that meaningfully improve patients' lives over existing therapies.
Superficial white matter analysis: An efficient point-cloud-based deep learning framework with supervised contrastive learning for consistent tractography parcellation across populations and dMRI acquisitions
Authors: Tengfei Xue, Fan Zhang, Chaoyi Zhang, Yuqian Chen, Yang Song, Alexandra J. Golby, Nikos Makris, Yogesh Rathi, Weidong Cai, Lauren J. O’Donnell
Journal: Medical Image Analysis (2023)
Risk of liver fibrosis associated with long-term methotrexate therapy may be overestimated
Authors: Edmond Atallah, Jane I. Grove, Colin Crooks, Esther Burden-Teh, Abhishek Abhishek, Sulleman Moreea, Kelsey M. Jordan, Aftab Ala, David Hutchinson, Richard J. Aspinall, Ruth Murphy, Guruprasad P. Aithal
Journal: Journal of Hepatology (2023)

BackgroundThe risk of significant liver fibrosis from prolonged methotrexate (MTX) exposure has been estimated in around 5% of patients, which has led to intensive monitoring strategies. However, the evidence is derived from retrospective studies that underreported risk factors of liver disease. We evaluated the risk of long-term MTX therapy on liver fibrosis in a longitudinal cohort study using two non-invasive markers.MethodBetween 2014-2021, adult patients diagnosed with Rheumatoid Arthritis (RA) or psoriasis for ≥2 years were recruited prospectively from six UK sites. MTX group included patients who received MTX for ≥6 months, whereas unexposed group included those who never received MTX. All patients underwent full liver profiling, enhanced liver fibrosis (ELF) markers, and transient elastography (TE).Results999 patients (mean age 60.8 ± 12 years, 62.3 % females) were included. Of 976 with valid TE values, 149 (15.3 %) had liver stiffness ≥7.9 kPa. Of 892 with valid ELF, 262 (29.4 %) had ELF ≥9.8. Age and BMI were independently associated with elevated liver stiffness and ELF. Neither MTX cumulative dose nor duration was associated with elevated liver stiffness. Diabetes was the most significant risk factor associated with liver stiffness ≥7.9 kPa (adjusted OR = 3.19, 95% CI 1.95 – 5.20, P <0.001). Regular use of non-steroidal anti-inflammatory drugs showed the strongest association with ELF ≥9.8 (OR = 1.76, 95% CI 1.20 – 2.56, P =0.003), suggesting the degree of joint inflammation in RA may confound ELF as a non-invasive marker of liver fibrosisConclusionThe risk of liver fibrosis attributed to MTX itself might have been previously overestimated; there is a need to consider modifying current MTX therapy monitoring guidelines.
The effect of guideline-based antimicrobial therapy on the outcome of fracture-related infections (EAT FRI Study)
Authors: Ruth Corrigan, Jonathan Sliepen, Rob J Rentenaar, Frank IJpma, Falco Hietbrink, Bridget L Atkins, Maria Dudareva, Geertje AM Govaert, Martin A McNally, Marjan Wouthuyzen-Bakker
Journal: Journal of Infection (2023)

This study investigated the compliance with a guideline-based antibiotic regimen on the outcome of patients surgically treated for a fracture-related infection (FRI).In this international multicenter observational study, patients were included when diagnosed with an FRI between 2015 and 2019. FRI was defined according to the FRI consensus definition. All patients were followed for at least one year. The chosen antibiotic regimens were compared to the published guidelines from the FRI Consensus Group and correlated to outcome. Treatment success was defined as the eradication of infection with limb preservation.A total of 433 patients (mean age 49.7 ± 16.1 years) with FRIs of mostly the tibia (50.6%) and femur (21.7%) were included. Full compliance of the antibiotic regime to the published guidelines was observed in 107 (24.7%) cases. Non-compliance was mostly due to deviations from the recommended dosing, followed by the administration of an alternative antibiotic than the one recommended or an incorrect use or non-use of rifampin. Non-compliance was not associated with a worse outcome: treatment failure was 12.1% in compliant versus 13.2% in non-compliant cases (p = 0.87).We report good outcomes in the treatment of FRI and demonstrated that minor deviations from the FRI guideline are not associated with poorer outcomes.
Measures of Food Inadequacy and Cardiovascular Disease Risk in Black Individuals in the US From the Jackson Heart Study
Authors: Rani Zierath, Brian Claggett, Michael E. Hall, Adolfo Correa, Sharrelle Barber, Yan Gao, Sameera Talegawkar, Edith I. Ezekwe, Katherine Tucker, Ana V. Diez-Roux, Mario Sims, Amil M. Shah
Journal: JAMA Network Open (2023)

Importance Food insecurity disproportionately affects Black individuals in the US. Its association with coronary heart disease (CHD), heart failure (HF), and stroke is unclear. Objective To evaluate the associations of economic food insecurity and proximity with unhealthy food options with risk of incident CHD, HF, and stroke and the role of diet quality and stress. Design, Setting, and Participants This cohort study was a time-to-event analysis of 3024 Black adult participants in the Jackson Heart Study (JHS) without prevalent cardiovascular disease (CVD) at visit 1 (2000-2004). Data analysis was conducted from September 1, 2020, to November 30, 2021. Exposures Economic food insecurity, defined as receiving food stamps or self-reported not enough money for groceries, and high frequency of unfavorable food stores (&amp;amp;gt;2.5 unfavorable food stores [fast food restaurants, convenience stores] within 1 mile). Main Outcomes and Measures The main outcomes were incident CVD including incident CHD, stroke, and HF with preserved ejection fraction and with reduced ejection fraction (HFrEF). During a median follow-up of 13.8 (IQR, 12.8-14.6) years, the associations of measures of food inadequacy with incident CVD (CHD, stroke, and HF) were assessed using multivariable Cox proportional hazards regression models. Results Among the 3024 study participants, the mean (SD) age was 54 (12) years, 1987 (66%) were women, 630 (21%) were economically food insecure, and 50% (by definition) had more than 2.5 unfavorable food stores within 1 mile. In analyses adjusted for cardiovascular risk and socioeconomic factors, economic food insecurity was associated with higher risk of incident CHD (hazard ratio [HR], 1.76; 95% CI, 1.06-2.91) and incident HFrEF (HR, 2.07; 95% CI, 1.16-3.70), but not stroke. These associations persisted after further adjustment for diet quality and perceived stress. In addition, economic food insecurity was associated with higher high-sensitivity C-reactive protein and renin concentrations. High frequency of unfavorable food stores was not associated with CHD, HF, or stroke. Conclusions and Relevance The findings of this cohort study suggest that economic food insecurity, but not proximity to unhealthy food options, was associated with risk of incident CHD and HFrEF independent of socioeconomic factors, traditional cardiovascular risk factors, diet quality, perceived stress, and other health behaviors. Economic food insecurity was also associated with markers of inflammation and neurohormonal activation. Economic food insecurity may be a promising potential target for the prevention of CVD.
Artificial Neural Network Modeling to Predict Neonatal Metabolic Bone Disease in the Prenatal and Postnatal Periods
Authors: Honglin Jiang, Jialin Guo, Jing Li, Chunlin Li, Wenchong Du, Federico Canavese, Charlie Baker, Hao Ying, Jing Hua
Journal: JAMA Network Open (2023)

Importance Early recognition of metabolic bone disease (MBD) in infants is necessary but difficult; an appropriate tool to screen infants at risk of developing MBD is needed. Objectives To develop a predictive model for neonates at risk for MBD in the prenatal and postnatal periods and detect the pivotal exposed factors in each period. Design, Setting, and Participants A diagnostic study was conducted from January 1, 2012, to December 31, 2021, in Shanghai, China. A total of 10 801 pregnant women (singleton pregnancy, followed up until 1 month after parturition) and their infants (n = 10 801) were included. An artificial neural network (ANN) framework was used to build 5 predictive models with different exposures from prenatal to postnatal periods. The receiver operating characteristic curve was used to evaluate the model performance. The importance of each feature was examined and ranked. Results Of the 10 801 Chinese women who participated in the study (mean [SD] age, 29.7 [3.9] years), 7104 (65.8%) were local residents, 1001 (9.3%) had uterine scarring, and 138 (1.3%) gave birth to an infant with MBD. Among the 5 ANN models, model 1 (significant prenatal and postnatal factors) showed the highest AUC of 0.981 (95% CI, 0.970-0.992), followed by model 5 (postnatal factors; AUC, 0.977; 95% CI, 0.966-0.988), model 4 (all prenatal factors; AUC, 0.850; 95% CI, 0.785-0.915), model 3 (gestational complications or comorbidities and medication use; AUC, 0.808; 95% CI, 0.726-0.891), and model 2 (maternal nutritional conditions; AUC, 0.647; 95% CI, 0.571-0.723). Birth weight, maternal age at pregnancy, and neonatal disorders (anemia, respiratory distress syndrome, and septicemia) were the most important model 1 characteristics for predicting infants at risk of MBD; among these characteristics, extremely low birth weight (importance, 50.5%) was the most powerful factor. The use of magnesium sulfate during pregnancy (model 4: importance, 21.2%) was the most significant predictor of MBD risk in the prenatal period. Conclusions and Relevance In this diagnostic study, ANN appeared to be a simple and efficient tool for identifying neonates at risk for MBD. Combining prenatal and postnatal factors or using postnatal exposures alone provided the most precise prediction. Extremely low birth weight was the most significant predictive factor, whereas magnesium sulfate use during pregnancy could be an important bellwether for MBD before delivery.
Evaluation of Faculty Parental Leave Policies at Medical Schools Ranked by <i>US News &amp; World Report</i> in 2020
Authors: Jessica Slostad, Shikha Jain, Marie McKinnon, Sukarn Chokkara, Neda Laiteerapong
Journal: JAMA Network Open (2023)

Importance Physician parents, particularly women, are more likely to experience burnout, poor family-career balance, adverse maternal and fetal outcomes, and stigmatization compared with nonparent colleagues. Because many physicians delay child-rearing due to the rigorous demands of medical training, favorable parental leave policies for faculty physicians are crucial to prevent physician workforce attrition. Objective To evaluate paid and unpaid parental leave policies at medical schools ranked by US News &amp;amp;amp; World Report in 2020 and identify factors associated with leave policies. Design, Setting, and Participants This cross-sectional national study was performed at US medical schools reviewed from December 1, 2019, through May 31, 2020, and February 1 through March 31, 2021, due to the COVID-19 pandemic. All medical schools ranked by US News &amp;amp;amp; World Report in 2020 were included. Main Outcomes and Measures The primary outcome was the number of weeks of paid and unpaid leave for birth, nonbirth, adoption, and foster care physician parents. Institutional policies for the number of weeks of leave and requirements to use vacation, sick, or disability leave were characterized. Institutional factors were evaluated for association with the duration of paid parental leave using χ 2 tests. Results Among the 90 ranked medical schools, 87 had available data. Sixty-three medical schools (72.4%) had some paid leave for birth mothers, but only 13 (14.9%) offered 12 weeks of fully paid leave. While 11 medical schools (12.6%) offered 12 weeks of full paid leave for nonbirth parents, 38 (43.7%) had no paid leave for nonbirth parents. Adoptive and foster parents had no paid leave in 35 (40.2%) and 65 (74.7%) medical schools, respectively. Median paid parental leave was 4 (IQR, 0-8) weeks for birth parents, 4 (IQR, 0-6) weeks for adoptive parents, 3 (IQR, 0-6) weeks for nonbirth parents, and 0 (IQR, 0-1) weeks for foster parents. About one-third of medical schools required birth mothers to use vacation (29 [33.3%]), sick leave (31 [35.6%]), or short-term disability (9 [10.3%]). Among institutional characteristics, higher ranking (top vs bottom quartile: 30.4% vs 4.0%; P = .03) and private designation (private vs public, 23.5% vs 9.4%; P &amp;amp;lt; .001) was associated with a higher rate of 12 weeks of paid leave for birth mothers. Conclusions and Relevance In this cross-sectional national study of medical schools ranked by US News &amp;amp;amp; World Report in 2020, many physician faculty receive no or very limited paid parental leave. The lack of paid parental leave was associated with higher rates of physician burnout and work-life integration dissatisfaction and may further perpetuate sex, racial and ethnic, and socioeconomic disparities in academic medicine.
Efficacy and Safety of Proposed Biosimilar Natalizumab (PB006) in Patients With Relapsing-Remitting Multiple Sclerosis
Authors: Bernhard Hemmer, Heinz Wiendl, Karsten Roth, Hendrik Wessels, Josef Höfler, Cyrill Hornuss, Bernd Liedert, Krzysztof Selmaj
Journal: JAMA Neurology (2023)

Proposed biosimilar natalizumab (biosim-NTZ) PB006 is the first biosimilar monoclonal antibody therapy developed for multiple sclerosis (MS) treatment.To evaluate matching efficacy, safety, and immunogenicity between biosim-NTZ and reference natalizumab (ref-NTZ) in patients with relapsing-remitting MS (RRMS).The Antelope trial was a phase 3, parallel-group, randomized, active-controlled study, conducted between October 2019 and March 2021, with last patient follow-up visit on August 23, 2021. The study took place in 48 centers in 7 countries. Of 531 patients with RRMS aged 18 to 60 years screened, 266 were excluded before randomization in line with study criteria. Eligible participants had 1 or more documented relapse within the previous year and either 1 or more gadolinium-enhancing T1-weighted or 9 or more T2-weighted brain lesions, Kurtzke Expanded Disability Status Scale score of 0 to 5.0 (inclusive), and John Cunningham virus index of 1.5 or less at screening. One patient withdrew consent before dosing.Intravenous infusions every 4 weeks of biosim-NTZ, 300 mg, or ref-NTZ, 300 mg (1:1 randomization), from week 0 to week 44 (end-of-study visit: week 48). At week 24, the ref-NTZ group was rerandomized and 30 patients were switched to biosim-NTZ for the remainder of the study.The primary end point was the cumulative number of new active lesions on magnetic resonance imaging (new gadolinium-enhancing T1-weighted lesions and new/enlarging T2-weighted lesions without double counting) over 24 weeks. Additional end points included further magnetic resonance imaging parameters, annualized relapse rate, and Kurtzke Expanded Disability Status Scale score. Safety, tolerability, and immunogenicity assessments included adverse events, laboratory evaluations, and positivity for anti-John Cunningham virus antibodies and antinatalizumab antibodies.A total of 264 participants (mean [SD] age, 36.7 [9.38] years; 162 [61.4%] female) received treatment with biosim-NTZ (n = 131) or ref-NTZ (n = 133). At week 24, the model-based mean difference in cumulative number of new active lesions between biosim-NTZ and ref-NTZ treatment groups was 0.17 (least square means [SE]: biosim-NTZ, 0.34 [0.34]; ref-NTZ, 0.45 [0.28]; 95% CI, -0.61 to 0.94 within the prespecified margins of ±2.1). No significant differences between treatment groups were observed across secondary efficacy end points, safety, tolerability, or immunogenicity assessments.Biosim-NTZ matched ref-NTZ in efficacy, safety, and immunogenicity for patients with RRMS in the tested setting. This phase 3 trial supports proposed biosim-NTZ as a biosimilar alternative to ref-NTZ for treating RRMS.ClinicalTrials.gov Identifier: NCT04115488.
Association of State Expansion of Supplemental Nutrition Assistance Program Eligibility With Rates of Child Protective Services–Investigated Reports
Authors: Anna E. Austin, Meghan E. Shanahan, Madeline Frank, Rebecca B. Naumann, H. Luz McNaughton Reyes, Giselle Corbie, Alice S. Ammerman
Journal: JAMA Pediatrics (2023)

States in the US have the option to eliminate the asset test and/or increase the income limit for Supplemental Nutrition Assistance Program (SNAP) eligibility under a policy called broad-based categorical eligibility (BBCE). Given associations of economic hardships, including food insecurity, with child protective services (CPS) involvement, state adoption of these policies may be associated with changes in rates of CPS-investigated reports.